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The house dust mite is the principal source of perennial aeroallergens in man. How these allergens activate innate and adaptive immunity is unclear, and therefore, there are no therapies targeting mite allergens. Here, we show that house dust mite extract activates store-operated Ca2+ channels, a common signaling module in numerous cell types in the lung. Activation of channel pore-forming Orai1 subunits by mite extract requires gating by STIM1 proteins. Although mite extract stimulates both protease-activated receptor type 2 (PAR2) and PAR4 receptors, Ca2+ influx is more tightly coupled to the PAR4 pathway. We identify a major role for the serine protease allergen Der p3 in stimulating Orai1 channels and show that a therapy involving sub-maximal inhibition of both Der p3 and Orai1 channels suppresses mast cell activation to house dust mite. Our results reveal Der p3 as an important aeroallergen that activates Ca2+ channels and suggest a therapeutic strategy for treating mite-induced asthma.

Original publication

DOI

10.1016/j.molcel.2018.03.025

Type

Journal article

Journal

Mol Cell

Publication Date

19/04/2018

Volume

70

Pages

228 - 241.e5

Keywords

Orai1, allergen, calcium channel, calcium release, house dust mite, mast cell, serine protease, store-operated calcium entry, Animals, Antigens, Dermatophagoides, Arthropod Proteins, Asthma, Calcium Signaling, Cell Movement, HEK293 Cells, Humans, Inhalation Exposure, Inositol 1,4,5-Trisphosphate, Ion Channel Gating, Jurkat Cells, Mast Cells, Mice, Inbred C57BL, Nasal Mucosa, Neoplasm Proteins, ORAI1 Protein, Pyroglyphidae, Receptors, G-Protein-Coupled, Receptors, Thrombin, Serine Endopeptidases, Stromal Interaction Molecule 1